We have demonstrated that COX-1 and COX-2 deficiencies reduce skin tumorigenesis and have shown that this reduction is due to altered differentiation. More recently we have demonstrated that COX-1 and COX-2 selective inhibitors alter epidermal differentiation just as observed in the respective COX deficient mice. By IHC of keratins in the epidermis, we have demonstrated differences in keratinocyte differentiation between the wild type and COX null mice or COX inhibitor treated mice. The basal keratinocytes of COX deficient and inhibitor treated mice began terminal differentiation prematurely, as K1 and K10 are expressed in a high percentage of these cells compared to wild type mice. This premature onset of terminal differentiation would continually remove initiated cell from the replicative population and decrease tumor growth and numbers. Surprisingly, apoptosis of keratinocytes in the COX deficient mice or inhibitor treated keratinocytes was not significantly increased compared to the level observed in wild type mice. Thus, the data suggest that altered terminal differentiation of keratinocytes may be a COX dependent mechanism by which NSAIDs reduce skin tumorigenesis.